Process for the preparation of penem compounds

ABSTRACT

Compound I ##STR1## is obtained by reaction of compound II  with compound III

This application is a continuation of application Ser. No. 07/515,234, filed Apr. 27, 1990 now abandoned.

The invention relates to a process for the preparation of penem compounds.

Penem derivatives of the formula I are valuable compounds with antibiotic properties. A synthetic process disclosed in the literature for penem derivatives I entails intramolecular cyclization of azetidinone derivatives of the formula II with trialkyl phosphites. However, this process often provides only poor yields. Moreover, the reaction is slow and requires elevated reaction temperatures, for example reflux in toluene. Under these reaction conditions there is frequently partial inversion of configuration at C-5, which results in undesired (5S,6S)-penems.

It has now been found that the described disadvantages of the known process can be avoided if dialkyl alkylphosphonites are used in place of trialkyl phosphites for the cyclization reaction. These novel reagents permit the reaction temperatures to be lower, for example room temperature, and result in shorter reaction times. Higher yields and purer products are achieved thereby. In addition, the undesired isomerization to (5S,6S)-penems is avoided. The dialkyl alkylphosphonates and dialkyl alkylthiophosphonates formed as by-products can be removed in a straightforward manner.

Hence the invention relates to a process for the preparation of penem derivatives of the formula I, in which the preferred configuration is (5R,6S) ##STR2## and in which R¹ denotes hydrogen, (C₁ -C₄)-alkyl, (C₁ -C₁₂)-alkoxy, (C₁ -C₁₂)-alkylthio, phenoxy, phenyl (the phenyl rings being unsubstituted or substituted once or twice by carboxyl, (C₁ -C₄)-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C₁ -C₄))-alkylaminocarbonyl, cyano, F, Cl or Br), (C₃ -C₆)-cycloalkyl, (C₃ -C₆)-cycloalkyloxy, (C₅ -C₆)-oxacycloalkyl (saturated or singly or doubly unsaturated), (C₃ -C₆)-oxocycloalkyl, (C₃ -C₆)-[1,1-bis(C₁ -C₃)-alkyloxy]-cycloalkyl, (C₃ -C₆)-[(C₁ -C₃)-alkylimino]-cycloalkyl, (C₃ -C₆)-[arylimino]cycloalkyl, (C₃ -C₆)-hydroxyiminocycloalkyl, (C₃ -C₆)-(C₁ -C₃ -alkyloxyimino)-cycloalkyl, in which the cycloalkyl radical is unsubstituted or substituted once or twice by C₁ -C₃ -alkyl, preferably methyl, by (C₁ -C₃)alkoxy, preferably methoxy, by halogen, preferably chlorine, or by methylene and is saturated or can contain one or two double bonds,

R² denotes hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically,

R³ denotes hydrogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkenyl, (C₁ -C₄)-alkoxy, (C₄ -C₇)-cycloalkyl, phenyl, 2-oxo-1,3-dioxolyl, triazolyl, thiazolyl, amino, acylamino or alkoxy.

Suitable and particularly preferred substituents are the following:

R¹ hydrogen, (C₁ -C₄)-alkyl (for example methyl, ethyl, hydroxymethyl and aminomethyl), (C₁ -C₄)-alkoxy (for example methoxy and ethoxy), (C₁ -C₃)-alkylthio (for example methylthio, ethylthio and propylthio), phenoxy (for example 4-carboxamidophenoxy or 4-cyanophenoxy), phenyl (for example 4-carboxamidophenyl or 4-cyanophenyl), saturated or unsaturated (C₅ -C₆)-oxacycloalkyl (for example tetrahydrofuryl or furyl), (C₅ -C₆)-oxocycloalkyl (for example 1-oxo-3-cyclobutyl), 3-hydroxyiminocyclobutyl, 3-methoxyiminocyclobutyl and 3,3-dimethoxycyclobutyl.

R³ 1-hydroxyethyl (in which the OH group is free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethyloxycarbonyl or 4-nitrobenzyloxycarbonyl), (C₁ -C₃)-alkoxy (for example methoxy or ethoxy), (C₁ -C₃)-alkenyl, for example triazolylethylene or thiazolylethylene.

The (C₁ -C₄)-alkyl and (C₁ -C₄)-alkoxy groups in the substitutent R¹ are either unsubstituted or substituted once or twice by hydroxyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-acyloxy, amino, (C₁ -C₄)-alkylamino, (C₁ -C₄)-acylamino, mercapto, (C₁ -C₄)-aIkylthio or heterocyclylthio, for example thiazolyl-, thiadiazolyl-, pyridylthio.

Phenyl nuclei are likewise unsubstituted or substituted once or twice by carboxyl, (C₁ -C₄)-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C₁ -C₄)-alkylaminocarbonyl, cyano or halogen, preferably F, Cl, Br.

The (C₁ -C₄)-alkyl and (C₁ -C₄)-alkoxy groups in R³ are either unsubstituted or substituted by hydroxyl, (C₁ -C₄)-alkoxy, (C₁ -C₄)-acyloxy, amino, (C₁ -C₄)-alkylamino, (C₁ -C₄)-acylamino, mercapto, (C₁ -C₄)-alkylthio or heterocyclylthio, it being possible for an OH group to be free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl.

In the process according to the invention, the compounds of the formula I are prepared by reacting a compound of the formula II ##STR3## in which X denotes oxygen or sulfur, and

R¹, R² and R³ have the above meaning, with a trivalent organic phosphorus compound of the formula III ##STR4## in which R⁶ denotes (C₁ -C₄)-alkyl, for example methyl, ethyl or trifluoromethyl, phenyl which can be substituted by (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy, and

R⁴ and R⁵ are identical or different and denote (C₁ -C₄)-alkyl, allyl, benzyl, or phenyl which can be substituted by (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy.

The reaction between a compound II and a compound III can be carried out in a suitable organic solvent, for example in tetrahydrofuran, ethyl acetate, an aromatic hydrocarbon such as benzene, toluene or xylene, or a halogenated hydrocarbon such as dichloromethane, trichloromethane or 1,1,2-trichloroethane.

The reaction temperature can vary between +10° C. and 160° C., preferably between +20° C. and +70° C.

The concentration of the compound II to be cyclized is between 1 mmol/l and 100 mmol/l, preferably between 2 mmol/l and 20 mmol/l.

The amount of the compound III can be between 2 and 8 mole-equivalents, preferably between 2 and 6 mole-equivalents, relative to II.

The compounds of the formulae II and III are known or can be prepared by processes disclosed in the literature.

The examples which follow serve to illustrate the invention further.

EXAMPLE 1 4-Nitrobenzyl (5R,6S)-6-[(1R)-tert.-butyldimethylsilyloxyethyl]-2-(4-aminocarbonylphenoxy)penem-3-carboxylate

130 mg (0.2 mmol) of (3S,4R)-4-[(aminocarbonyl)-phenoxythiocarbonylthio]-3-[(1R)-tert.-butyldimethylsilyloxyethyl)]-1-(4-nitrobenzyloxycarbonyl)-azetidin-2-one were dissolved in 90 ml of CHCl₃ under an argon atmosphere at 55° C. To this was added within 30 minutes a solution of 90 mg (0.8 mmol) of dimethyl methylphosphonite CH₃ P(OCH₃)₂ in 10 ml of CHCl₃, and, after addition was complete, the mixture was then stirred for 2 hours and, after cooling, worked up. Extraction with 1N NaHCO₃ solution, 1N KHSO₄ solution and water was carried out, and the organic phase was dried with magnesium sulfate and concentrated in vacuo. The crude product provided, after flash chromatography (SiO₂ 70-200 μm+10% H₂ O; first toluene+ethyl acetate 20+1, then 1+1 for elution), the title compound in 83% yield.

The compounds I listed in Table 1 were obtained analogously from the starting substances II listed in Table 2 under the reaction conditions listed in Table 3.

      NMR - data on the penem I according to the invention       ##STR5##        Example R.sup.1 R.sup.2 R.sup.3 .sup.1 H-NMR (CDCl.sub.3) : δ      (ppm)       1      ##STR6##       PNB CH(OTBDMS)CH.sub.3 8.17, 7.55(4H, AA'BB', J=8.7Hz,aromat. H of      PNB); 7.83, 7.21(4H AA'BB',J=8.8 aromat. H of benzamide); 5.65(1H,      d,J=1.4, H-5); 5.38, 5.21(2H, AB, J=13.8,Benzyl-H); 4.41-4,42(1H, m,      CH(OTBDMS));3.76(1H, dd J=1.4, 4.8, H-6); 1.25(3H, d,J=6.2, CH.sub.3 );      0.82(9H, s. tert.-Butyl-H);0.09, 0.05(6H, 2×s, Si(CH.sub.3).sub.2).       2      ##STR7##       CH.sub. 2 CHCH.sub.2 " 7.83, 7.21(4H, AA'BB', J=8.8, aromat. Hof      benzamide); 5.78-5.94(1H, m, CH); 5.62(1H, d, J=1.4, H-5); 5.40-5.17(2H,      m, CH.sub.2);4.66(2H, m, CO.sub.2 CH.sub.2); 4.25(1H, m,CH(OTBDMS));      3.71(1H, dd J=1.4, 4.8, H-6); 1.25(3H, d, J=6.2, CH.sub.3 ); 0.88(9H,      s,tert.-Butyl-H); 0.09, 0.05(6H, 2×s,Si(CH.sub.3).sub.2).   3       ##STR8##       CH.sub.2 CH.sub.2 SiMe.sub.3 " 7.82, 7.20(4H, AA'BB', J=8.8, aromat.      Hof benzamide); 5.61(1H, d, J=1.4, H-5);4.20-4.30(3H, m, CH(OTBDMS) and      CO.sub.2 CH.sub.2);3.72(1H, dd J=1.4, 4.8, H-6); 1.25(3H, d,J=6.2,      CH.sub.3 ); 0.96(2H, m, CH.sub.2 Si); 0.87(9H,s, tert.-Butyl-H);      0.1-0.01(total 15H, 3×s,Si(CH.sub.3).sub.3).   4 OCH.sub.3      CH.sub.2 CHCH.sub.2 CH(OTBDMS)CH.sub.3 5.85-6.02(1H, m, CH); 5.55(1H, d,          J=1.4, H-5); 5.43-5.17(total 2H, m, CH.sub.2);     4.65(2H, m,      CO.sub.2 CH.sub.2); 4.25(1H, m,     CH(OTBDMS)); 4.00(3H, s, OCH.sub.3);      3.65(1H,     dd, J=1.4, 4.8, H-6); 1.25(3H, d, J=6.2,     CH.sub.3 );      0.90(9H, s, tert.-Butyl-H); 0.10(6H,     2×s, Si(CH.sub.3).sub.2).        5 OCH.sub.3 PNB " 8.20, 7.60(4H, AA'BB, J=8.7Hz, aromat. H     of      PNB); 5.61(1H, d, J=1.4, H-5); 5.39 and     5.19(2H, ABq, 14Hz, Benzyl-H)      ; 4.25(1H, m,     CH(OTBDMS)); 4.04(3H, s, OCH.sub.3); 3.71(1H,     dd,      J=1.4, 4.8, H-6); 1.27(3H, d, J=6.2,     CH.sub.3 ); 0.82(9H, s,      tert.-Butyl-H); 0.09,     0.05(6H, 2×s, Si(CH.sub.3).sub.2).   6      OCH.sub.3 CH.sub.2 CH.sub.2 SiMe.sub.3 " 5.52(1H, d, J=1.4, H-5);      4.25(total 3H, m,     CH(OTBDMS), CH.sub.2        OCO); 4.00(3H, s, OCH.sub.3),     3.65(1H, dd J=1.4, 4.8, H-6);      1.25(3H, d,     J=6.2, CH.sub.3 ); 1.05(2H, m, CH.sub.2 Si); 0.90(9H,       s, tert.-Butyl-H); 0.5-0.1(15H, 3×s,     Si(CH.sub.3).sub.3).   7       ##STR9##       PNB " 8.29, 7.59(4H, AA'BB', J=8.7Hz, aromat. Hof PNB); 5.55(1H, d,      J=1.4, H-5); 5.39 and5.19(2H, ABq, 14Hz, Benzyl-H); 4.72(1H, m,1'CH);      4.25(1H, m, CH(OTBDMS)); 3.66(1H,dd J=1.4, 4.8, H-6); 2.0-1.5(total 8H,      m,Cyclopentyl-CH.sub.2); 1.27(3H, d, J=6.2, CH.sub.3 );0.82(9H, s,      tert.-Butyl-H); 0.08, 0.05(6H,2×s, Si(CH.sub.3).sub.2).   8       ##STR10##       PNB CH(OTBDMS)CH.sub.3 8.19, 7.61(4H, AA'BB', J=8.7Hz, aromat. Hof      PNB); 5.55(1H, d, J=1.4, H-5); 5.29 and5.19(2H, ABq, 14Hz, Benzyl-H);      4.21-4-12(total 3H, m, 1'-CH and CH(OTBDMS)); 3.66(1H, dd, J= 1.4, 4.8,      H-6); 2.05-1.3(total10H, m, Cyclohexyl-CH.sub.2); 1.27(3H, d, J=6.2,CH.su      b.3       ); 0.82(9H, s, tert.-Butyl-H);0.08,0.05(6H, 2×s, Si(CH.sub.3).sub.      2).   9 SCH.sub.3 CH.sub.2 CHCH.sub.2 " 5.85-6.02(1H, m, CH); 5.61(1H,      d,     J=1.4, H-5); 5.43, 5.37, 5.22, 5.19(total 2H,     4×d,      CH.sub.2); 4.70(2H, m, CO.sub.2 CH.sub.2); 4.22     (1H, m, CH(OTBDMS));      3.68(1H, dd J=1.4,     4.8, H-6); 2.51(3H, s, SCH.sub.3); 1.23(3H, d,       J=6.2, CH.sub.3); 0.88(9H, s, tert.-Butyl-H);     0.10(6H, 2×s,      Si(CH.sub.3).sub.2).  10 SCH.sub.3 PNB " 8.21, 7.51(4H, AA'BB', J=8.7Hz,      aromat. H     of PNB); 5.66(1H, d, J=1.4, H-5); 5.41 and     5.21(2H,      ABq, 14Hz, Benzyl-H); 4.25(1H, m,     CH(OTBDMS)); 3.71, 1H, dd j=1.4,      4.8, H-6);     2.52(3H, s, SCH.sub.3); 1.25(3H, d, J= 6.2,     CH.sub.3      ); 0.82(9H, s, tert.-Butyl-H); 0.09,     0.05(6H, 2×s, Si(CH.sub.3)      .sub.2).  11 SCH.sub.3 CH.sub.2 CH.sub.2 SiMe.sub.3 " 5.59(1H, d, J=1.4,      H-5); 4.0-4.31(zus.     3H, m, CH(OTBDMS), CH.sub.2 OCO); 3.66(1H, dd       J=1.4, 4.8, H-6); 2.50(3H, s, SCH.sub.3); 1.27     (3H, d, J=6.2,      CH.sub.3 ); 1.08(2H, m, CH.sub.2 Si);     0.89(9H, s, tert.-Butyl-H);      0.01-0.11(15H,     3×s, Si(CH.sub.3).sub.2).       12      ##STR11##       CH.sub.2 CH.sub.2 SiMe.sub.3 CH(OTBDMS)CH.sub.3 5.52 and 5.45(total 1H,      d, J=1.4, H-5);5.42-5.35(1H, m, 2' -CH); 4.31-4.15(total 13H,m, CH(OTBDMS      ) and CH.sub.2OCO); 4.03-3.77(2H,m, 5' -CH.sub.2); 3.64(1H, m, H-6);      2.51-2.34(1H,m, 3',4'-CH.sub.2); 2.05-1.71(3H, m, 3',4'-CH.sub.2);1.25(to      tal 3H, m, CH.sub.3 ); 1.08(2H, m, CH.sub.2 Si);0.87(9H, m, CH.sub.2 Si      and tert.-Butyl-H);0.09-0.11(15H, m, Si(CH.sub.3).sub.3).       13      ##STR12##       CH.sub.2 CH.sub.2 SiMe.sub.3 " 7.68, 7.52, 6.53(total 3H, 3×m,      Furyl-H);5.56(1H, d, J=1.4, H-5); 4.34-4.21(total 3H,m, CH(OTBDMS) and      CH.sub.2OCO); 3.69(1H, dd,J=1.4, 4.8, H-6); 1.28(3H, d, J=6.2, CH.sub.3      );1.10(2H, m, CH.sub.2 Si); 0.91(9H, m,tert.-Butyl-H); 0.01-0.11(15H,      3×s,Si(CH.sub.3).sub.3).       1415      ##STR13##       CH.sub.2 CH.sub.2 SiMe.sub.3 " 7.50, 7.39(total 15H, 2×m,      Phenyl-H); 5.69(1H, d, J=1.4, H-5); 4.31(1H, m,CH(OTBDMS)); 4.19(2H, m,      CH.sub.2OCO); 3.78(1H, dd, J=1.4, 4.8, H-6); 1.32(3H, d,J=6.2, CH.sub.3      ); 0.93(total 11H, m, CH.sub.2 Si andtert.-Butyl-H); 0.01-0.11(15H,      3×s,Si(CH.sub.3).sub.3).       16      ##STR14##       CH.sub.2 CH.sub.2 SiMe.sub.3 CH(OTBDMS)CH.sub.3 8.06, 7.53(4H, AA'BB,      J=8.8Hz, aromat. H);6.1-5.94(1H, m, CH); 5.71(1H, d, J=1.4,H-5);      5.44-5.20(2H, m, CH.sub.2); 4.84(2H, m,CO.sub.2 CH.sub.2 /Allyl);      4.27(1H, m, CH(OTBDMS));4.16(2H, m, CO.sub.2 CH.sub.2 /TMSE); 3.78(1H,      dd,J=1.4, 4.8, H-6); 1.28(3H, d, J=6.2, CH.sub.3       );0.91(9H, s, tert.-Butyl-H); 0.11-0.01(15H,4×s, Si(CH.sub.3).sub.      2).       17      ##STR15##       CH.sub.2 CH.sub.2       SiMe.sub.3 "      ##STR16##       18      ##STR17##       CH.sub.2       CHCH.sub.2 "      ##STR18##       19      ##STR19##       CH.sub.2 CH.sub.2       SiMe.sub.3 "      ##STR20##      *TBDMS = tbutyldimethylsilyl      Me = Methyl      PNB = paraNitrobenzyl      TCE = 1,1,2Trichloroethane      *Compound "14" is prepared from 2 different precursors in Example 14 and      15

                                      TABLE 2                                      __________________________________________________________________________     Starting compounds                                                              ##STR21##                                                                     Example                                                                             R.sup.1          R.sup.2  R.sup.3  X                                      __________________________________________________________________________           ##STR22##       PNB      CH(OTBDMS)                                                                              S                                      2                                                                                    ##STR23##       CH.sub.2 CHCH.sub.2                                                                     "        S                                      3                                                                                    ##STR24##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        S                                      4    OCH.sub.3        CH.sub.2 CHCH.sub.2                                                                     "        S                                      5    OCH.sub.3        PNB      "        S                                      6    OCH.sub.3        CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        S                                      7                                                                                    ##STR25##       PNB      "        S                                      8                                                                                    ##STR26##       PNB      "        S                                      9    SCH.sub.3        CH.sub.2 CHCH.sub.2                                                                     "        S                                      10   SCH.sub.3        PNB      "        S                                      11   SCH.sub.3        CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        S                                      12                                                                                   ##STR27##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        O                                      13                                                                                   ##STR28##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        O                                      14                                                                                   ##STR29##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        O                                      15                                                                                   ##STR30##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        S                                      16                                                                                   ##STR31##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        O                                      17                                                                                   ##STR32##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        O                                      18                                                                                   ##STR33##       CH.sub.2 CHCH.sub.2                                                                     "        O                                      19                                                                                   ##STR34##       CH.sub.2 CH.sub.2 SiMe.sub.3                                                            "        O                                      __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________     Reaction conditions for the cyclization reaction                                ##STR35##                                                                                           Conc.      Temp.                                         Example                                                                             Reagent III                                                                            Equivalents of III                                                                      (mmol/l)                                                                            Solvent                                                                              (°C.)                                                                       Reaction time (h)                                                                       Yield %                          __________________________________________________________________________     1    CH.sub.3 P(OCH.sub.3).sub.2                                                            4        20   CHCl.sub.3                                                                           55  2        83                               2    "       3        20   1.1.2-TCE                                                                            60  1        57                               3    "       4         2   CHCl.sub.3                                                                           "   2        62                               4    CH.sub.3 P(OC.sub.2 H.sub.5).sub.2                                                     4        20   "     "   0,5      38                               5    "       4        20   "     "   0,5      55                               6    "       4        20   "     "   0,5      48                               7    "       4         2   "     "   2        80                               8    "       4         2   "     "   3        70                               9    "       6        20   "     55  1        67                               10   "       6        20   "     "   1        61                               11   "       6        20   "     "   1        75                               12   "       4        20   "     60  3        37                               13   "       4        20   "     "   6        55                               14   "       5        20   "     55  1        25                               15   CH.sub.3 P(OCH.sub.3).sub.2                                                            4        20   "     60  0,5      20                               16   CH.sub.3 P(OC.sub.2 H.sub.5).sub.2                                                     4        20   "     "   1        55                               17   "       4        40   1.1.2-TCE                                                                            70  2,5      72                               18   "       4        40   "     "   2,5      58                               19   "       4        40   "     "   2,5      42                               __________________________________________________________________________ 

We claim:
 1. A process for the preparation of a penem compound I ##STR36## in which R¹ denotes hydrogen, (C₁ -C₄)-alkyl, (C₁ -C₁₂)-alkoxy, (C₁ -C₁₂)-alkylthio, phenoxy, phenyl (the phenyl rings being unsubstituted or substituted once or twice by carboxyl, (C₁ -C₄)-alkoxycarbonyl, allyloxycarbonyl, aminocarbonyl, (C₁ -C₄)-alkylaminocarbonyl, cyano, F, Cl or Br), (C₃ -C₆)-cycloalkyl, (C₃ -C₆)-cycloalkyloxy, (C₅ -C₆)-oxacycloalkyl (saturated or singly or doubly unsaturated), (C₃ -C₆)-oxocycloalkyl, (C₃ -C₆)-1,1-bis(C₁ -C₃)-alkyloxy]-cycloalkyl, (C₃ -C₆)-[(C₁ -C₃)-alkylimino]-cycloalkyl, (C₃ -C₆)-[arylimino]cycloalkyl, (C₃ -C₆)-hydroxyiminocycloalkyl, (C₃ -C₆)-(C₁ -C₃ -alkyloxyimino)-cycloalkyl, in which the cycloalkyl radical is unsubstituted or substituted once or twice by C₁ -C₃ -alkyl, by (C₁ -C₃)-alkoxy, by halogen, or by methylene and is saturated or can contain one or two double bonds,R² denotes hydrogen or a customary carboxyl protective group which can be eliminated by hydrolysis, photolysis, oxidation, reduction or enzymatically, R³ denotes hydrogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkenyl, (C₁ -C₄)-alkoxy,(C₄ -C₇)-cycloalkyl, phenyl, 2-oxo-1,3-dioxolyl, triazolyl, thiazolyl, amino, acylamino or alkoxy,which comprises reacting at between +10° C. and +70° C. a compound of the formula II ##STR37## in which X denotes oxygen or sulfur, and R¹, R² and R³ have the above meaning, with a trivalent organic phosphorus compound of the formula III ##STR38## in which R⁶ denotes (C₁ -C₄)-alkyl, phenyl which can be substituted by (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy, and R⁴ and R⁵ are identical or different and denote (C₁ -C₄)-alkyl, allyl, benzyl, or phenyl which can be substituted by (C₁ -C₃)-alkyl or (C₁ -C₃)-alkoxy.
 2. The process as claimed in claim 1, wherein the reaction of compound II with III is carried out in an organic solvent.
 3. The process as claimed in claim 1, whereinR¹ denotes hydrogen, (C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy, (C₁ -C₃)-alkylthio, phenoxy, phenyl (the phenyl nuclei being substituted by (C₁ -C₄)-alkoxycarbonyl, aminocarbonyl or cyano), (C₅ -C₆)-oxacycloalkyl, (C₄ -C₆)-oxocycloalkyl, 3-hydroxyiminocyclobutyl, 3-methoxyiminocyclobutyl, 3,3-dimethoxycyclobutyl, 3-methoxy-2-cyclobuten-1-yl, 2-methoxy-1-cyclobuten-1-yl and 4-methoxy-3-cyclohexen-1-yl R³ denotes 1-hydroxyethyl (in which the OH group is free or protected by trimethylsilyl, diphenyl-tert.-butylsilyl, allyloxycarbonyl, trichloroethoxycarbonyl or 4-nitrobenzyloxycarbonyl), (C₁ -C₃)-alkoxy, (C₁ -C₃)-alkenyl. 